Infection is a major problem affecting function and longevity of dialysis catheters. Catheter-related sepsis occurs at alarmingly high rates, and often necessitates intervention or catheter removal. This grant is evaluating the hypothesis that a covalently attached selenium coating can reduce bacterial colonization and biofilm formation on the surface of dialysis catheters, thereby lowering the incidence of device-centered infection. Selenium is an essential dietary requirement for humans. Selected selenium compounds are catalytic and produce superoxide radicals (O2-) by their reaction with thiols. High local concentrations of these superoxides cause lysis of bacterial cells, and could be particularly effective in preventing biofilm formation, since the mechanism of action for the superoxide does not require cells to be metabolically active. In fact, in one study, Se compounds were shown effective against 90% of clinically-isolated MRSA strains. Since it is catalytic, the covalently attached Se compound will remain on the surface and be active permanently, unlike conventional eluting coatings that are often gone within 30 days and that can elicit deleterious systemic effects. Additionally, since the superoxide radical has only a very short diffusion lifetime, the selenium coatings will be only locally active and will not adversely affect biocompatibility of the device with neighboring human cells. Phase I successfully demonstrated significant (>90%) reduction in biofilm formation for both gram positive (Staphylococcus aureus) and gram negative (Pseudomonas aeruginosa) bacteria on selenium coated polyurethane catheter material. Selenium coatings were attached to the surface utilizing a unique combination of plasma pre-treatment surface activation process followed by a chemical deposition step. Investigations of coating density revealed that the process can be tailored to control Se concentration on the surface. Following the successful Phase I project, Phase II will extend the results to produce a commercially viable anti-infective coating technology. A key objective in Phase II is coating processes optimization, where the goal is to determine optimal levels of selenium coating concentrations, considering antimicrobial efficacy, biocompatibility, and robustness of the process. Using both microtiter plate assays and a multi-cell flow-through continuous-culture system, the program will examine effectiveness of the coating against both single and dual-species biofilm formation. Coating stability will be monitored over long time periods to demonstrate ability of the technology to prevent infection in chronic applications. Finally, an animal model (murine) will be employed to demonstrate in vivo efficacy. This study will utilize bioluminescent strains of bacteria to permit dynamic assessment of biofilm formation for periods up to 25 days. Relevance: The proposed research is developing selenium coatings to reduce biofilm formation and device-centered infection on dialysis catheters. The coating could provide significant benefits to dialysis patients by preserving access and reducing secondary complications resulting from infected catheters. Due to the prevalence of dialysis catheter infection, an effective treatment could significantly impact cost of healthcare delivery for patients using catheters as their primary access. PUBLIC HEALTH RELEVANCE: Hemodialysis is a method of filtering blood of impurities in patients whose kidney function has either failed or has become severely diminished. The hemodialysis process uses an extracorporeal system to cleanse the patient's blood of toxins. Catheters are one of the methods used to provide the vascular access to these patients. Despite US Kidney Disease Outcome Quality Initiative (K/DOQI) guidelines which discourage cuffed, tunneled central venous catheters for permanent access the utilization of such catheters is increasing due to factors such as a higher incidence of co-morbid conditions that prevent forming and sustaining an AV fistula or other access method, and late referrals for vascular access. In fact, over 23% of hemodialysis patients were being dialyzed with a catheter at the end of 2004. There are currently about 300,000 chronic dialysis catheters sold annually comprising a $80-$100 million US market. Although catheters offer certain advantages, such as the ability to use them immediately, ease of insertion and replacement, and their almost universal applicability for dialysis patients, catheters have the highest rates of infection among the primary dialysis access methods. Numerous technologies have been investigated for addressing catheter infection, but none have successfully mitigated the problem. If successful, selenium coated catheters would provide significant benefits to dialysis patients by preserving access and reducing secondary complications resulting from infected catheters. Due to the prevalence of the infection problem in dialysis catheters, an effective coating could significantly impact cost of healthcare delivery for dialysis patients using catheters as their primary access. The technology would have immediate application for Spire's existing chronic hemodialysis catheter line. [unreadable] [unreadable] [unreadable]